Early atherosclerosis in humans: role of diffuse intimal thickening and extracellular matrix proteoglycans

Abstract

This review attempts to define the early events that lead to lesions of human atherosclerosis based on careful morphological studies in human autopsy specimens. In contrast to most small laboratory animals, diffuse intimal thickening (DIT) is present in human arteries before atherosclerosis develops, particularly in the atherosclerosis-prone arteries such as coronary arteries and abdominal aorta. In the earliest stage of atherosclerosis, lipids deposit eccentrically in the deep layer of DIT to form Type I lesions. These layers are enriched in extracellular matrix (ECM) proteoglycans such as biglycan. Following lipid deposition, macrophages appear in these regions and foam cells are observed (Type II lesions). Such observations support the 'response-to-retention' hypothesis that states that a principle early event in the pathogenesis of human atherosclerosis is the trapping and retention of lipoproteins by ECM proteoglycans followed by infiltration and accumulation of macrophages.

HDL and Atherothrombotic Vascular Disease

“…It is characterized by extracellular accumulation of cholesterol in the deep layers of the intima, i.e., below the superficial foam cell layers. However, in sharp contrast to the superficial layers of the intima, where atherogenesis initiates and where macrophages swiftly arrive and efficiently remove the lipids so preventing their extracellular accumulation, in the deep layers, the macrophages arrive late (Nakashima et al 2008). Accordingly, once formed, the deep extracellular lipids are not rapidly scavenged by macrophages.…”

Advanced Glycation Endproduct Changes to Bruch's Membrane Promotes Lipoprotein Retention by Lipoprotein Lipase

“…22,25 Gustaffson et al 41 have shown in mice that LDL retention is initiated by direct binding to proteoglycans but shifts to binding with LPL later in the disease. Proteoglycans are glycoproteins that contain a core protein with covalently attached glycosaminoglycans.…”

“…In atherosclerosis, the important and most abundant core proteins include biglycan, versican, and decorin. 25 The most abundant glycosaminoglycan side chains are chondroitin sulfate and dermatan sulfate, both of which are increased in atherosclerosis, as well as heparan sulfate. 42 Biglycan and versican have been extensively studied for their role in lipoprotein retention because they i) have strong affinity for chondroitin and dermatan sulfate proteoglycans, 42 ii) are enriched in areas of atherosclerosis, 42 and iii) bind to apoB100-containing lipoproteins.…”

“…22,25 We were particularly intrigued by biglycan because we previously identified a 1.4-fold increase in biglycan expression in the RPE/ choroid of mice treated with D-gal. 33 We, therefore, performed fluorescence IHC to determine whether these proteoglycans developed in Bruch's membrane after D-gal treatment.…”

“…These include an accumulation of certain matrix proteoglycans such as biglycan, decoran, and versican that retain lipoproteins due to their electronegative charge. 22,25 Secreted sphingomyelinases and LPL, which are distinct from hepatic lipase, endothelial lipase, and pancreatic lipase (PL), in the subendothelial matrix promote lipoprotein retention. 26 -28 The formation of advanced glycation endproducts (AGEs) also promotes lipoprotein retention within the subendothelial matrix.…”